Definition
- Familial Mediterranean Fever (FMF) is a rare disease, more common in patients from around the Mediterranean.
- Familial Mediterranean Fever (FMF) is a hereditary disease.
- Formerly known as periodic illness.
Epidemiology
- Familial Mediterranean Fever (FMF) affects less than one person in 2,000 in France, and is more common in certain populations around the Mediterranean.
- Familial Mediterranean Fever (FMF) affects both men and women.
- Symptoms of the disease usually begin in childhood.
Genetic
Familial Mediterranean Fever (FMF) is an autosomal recessive inherited disease which means that patients carry 2 mutations, one on each chromosome inherited from each parent. The mutated gene is called 'MEFV' for MEditerranean FeVer.
In very rare cases patients with a single mutation may express the disease, often a milder form.
The MEFV gene encodes a protein whose role is to produce inflammation to kill microbes.
In the countries around the Mediterranean, the frequency of mutations is high, particularly among Armenians, Turks, Sephardic Jews and Arabs.
Clinical
Familial Mediterranean Fever (FMF) develops in attacks lasting from 24 to 72 hours. The first symptoms of the disease appear very early in life: generally before the age of 5 in 75% of cases, and before the age of 1 in 10% of cases. The patient has no symptoms between attacks. The interval between attacks varies.
During attacks the fever is often high (38.5° and 39°C but can go up to 40°C) and may be preceded by a feeling of fatigue or malaise. Other signs may be associated with this fever. The most common being intense abdominal pain with an abdomen that may suggest appendicitis. Other symptoms are pain in the chest, knees or ankles and red edema of the ankles called pseudoerysipelas.
Some patients may have muscle pain, particularly in the legs, and more rarely mouth ulcers. The crises are often identical for the same individual but they can differ within a family.
Sometimes certain inflammatory diseases are associated, such as psoriasis, spondyloarthritis and Verneuil's disease.
Diagnostic
It is suspected on clinical criteria known as Livneh in adults and Yalcinkaya in children, then confirmed by a genetic study looking for a mutation in the MEFV gene, mainly in exon 10.
Evolution
Familial Mediterranean Fever (FMF) is not a serious disease in the sense that it does not usually reduce life expectancy these days, thanks to a highly effective and accessible treatment that keeps the disease well under control. However, if FMF progresses without treatment for several years, there is a risk of developing renal AA amyloidosis.
Treatment
Patients should receive regular treatment and follow-up.
Current treatment for Familial Mediterranean Fever (FMF) does not provide a cure.
Its objectives are to improve quality of life, reduce attacks or even eradicate them, normalize inflammatory markers (CRP, SAA) and avoid long-term complications which are mainly renal related to AA amyloidosis.
The reference treatment is colchicine, which will be started at 1 mg/day and adapted to the interictal CRP and the persistence or not of the attacks with the doctor. The maximum daily dose is 2.5 mg/day. The treatment is lifelong and effective in more than 95% of cases (prevents or alleviates attacks) and is usually well tolerated.
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In the event of resistance to colchicine, an extremely rare situation, anti-Interleukin 1 biotherapy may be proposed after consulting an expert reference centre:
It must be associated with the management of factors favoring crises, in particular stress management, the practice of regular gentle physical activity, etc.
Frequently asked questions
1. What is familial Mediterranean fever (FMF)?
Formerly called periodic illness, it is an inherited disease that belongs to the group of innate immunity diseases: auto-inflammatory diseases. It is considered a rare disease with less than 1 case in 2000 depending on the country. It affects preferentially people from the Mediterranean area. The prevalence (number of cases in a given population at a given time) of FMF is about 1/200 to 1/1000 in certain populations around the Mediterranean, about 100,000 cases worldwide and 5 to 10,000 cases in France. The first symptoms of the disease appear early in life: generally before 5 years of age in 75% of cases and before 1 year of age in 10% of cases. FMF does not manifest itself permanently but rather in the form of bouts or "attacks" of fever, often high (38.5°C and 39°C and up to 40°C) and accompanied by a feeling of malaise and cold (chills). The crisis can be announced by the onset of great fatigue and loss of appetite. It lasts on average 2 to 3 days. Along with fever, the most common sign is extreme abdominal pain (hard stomach sensation) that can lead to a "bent-over" position, with the legs tucked under the body or the torso bent forward to reduce pain. Because of the intensity of the pain and the appearance of the abdominal area, the attack can be mistaken for appendicitis or peritonitis, which is why it is important to know that you have FMF to avoid unnecessary surgery. Patients may also experience pain in the lungs, due to damage to the membrane that protects them, called the pleura, which manifests itself as chest pain, shoulder pain or difficulty breathing. Leg pain is very common in the muscles and joints, especially in the ankles and knees. The joints may sometimes swell due to arthritis. The FMF attack can also manifest itself by pain in the ankle with a red appearance of the skin in front of it called "pseudo erysipelas of the ankle". Outside of the attacks, it is common to feel pain in the calves, under the heels or under the soles of the feet during prolonged effort, with more rarely a localized swelling.
2. What causes FMF?
FMF is a genetic disease, which means that it is associated with a mutation in a gene, the MEFV gene (for MEditerranean FeVer). It is recessive, which means that in order to express the disease, patients carry 2 mutations of the MEFV gene, one inherited from each parent. Genes are carried by our chromosomes within all the cells of our body. They are used to program the production of proteins that are essential for the functioning of our body. In the case of the MEFV gene, it programs a protein, pyrin, whose role is to produce inflammation to eliminate microbes (intestinal microbes in particular). Patients with FMF have a mutation in this gene that causes them to produce much more inflammation than normal and inappropriately. Researchers have shown that this excess of inflammation would have been acquired to better fight against certain infections such as the Black Plague, which killed many people in the Middle Ages. This could explain the particular distribution of FMF around the Mediterranean.
3. How is FMF transmitted?
FMF is an autosomal recessive inherited disease (see question 4). It affects both men and women, and consanguinity increases the risk of transmitting the mutation (Figure 1). As shown in the figure below, the risk of having an affected child by parents who are healthy carriers (i.e. who have a single mutation and do not express the disease) is 1/4.
4. What is the cause of FMF?
FMF mainly affects people living around the Mediterranean. It appears to have appeared several thousand years ago in the Mesopotamian basin, in the region where Israel is located today (Figure 2). The number of sufferers remains much higher in the Armenian, Sephardic Jewish and Turkish populations. Today, FMF is found throughout the world, but in patients of Mediterranean origin.
5. How is FMF diagnosed?
The diagnosis of FMF is based on the notion of fever attacks as described above associated with the presence of inflammation in the blood. This is why a blood test will be prescribed during an attack to measure the inflammation with the dosage of CRP: C-reactive protein and a blood count to look for an increase in white blood cells including neutrophils. (The blood count is a simple blood test to count the number of red and white blood cells and platelets.) At present, a genetic test is available which allows to confirm the diagnosis of FMF in the vast majority of typical forms with 2 mutations. It consists in taking a blood sample in a city or hospital laboratory, after obtaining informed consent. The result of this test must be returned to the physician who ordered it and he will explain the results. In most cases where the clinical signs are typical and the patient belongs to an ethnic group at risk, there is no equivocation and the genetic diagnosis confirms the clinic. However, some cases are not genetically confirmed (as two mutations in the MEFV gene are theoretically required) and require an opinion by an FMF expert.
6. When should medical examinations be carried out to manage FMF? Which medical examinations?
As part of disease monitoring, inflammation (CRP) should be checked once or twice a year, and liver and kidney function should be monitored once a year by means of a blood test and urine analysis.
7. What triggers FMF attacks?
The factors that cause the attacks are known; they are emotions, stress, unusual physical activity, lack of sleep, menstruation, cold or hot weather, and sometimes even certain foods like chocolate.
8. How is FMF evolving?
FMF is a chronic disease that progresses in attacks/flare-ups, potentially for life, although it may subside with age. Prolonged inflammation can lead to complications, the most serious of which is inflammatory amyloidosis (IA), which primarily affects the kidneys. Daily intake of the basic treatment (Colchicine) allows to reduce the number of attacks or even to eradicate them.
9.What is the risk of developing AA amyloidosis?
FMF can be complicated by inflammatory amyloidosis or AA amyloidosis. Amyloidosis results from the deposition in certain organs of an inflammatory protein called SAA (which is an equivalent of C-reactive protein or CRP). The risk of developing amyloidosis is globally proportional to the degree and duration of inflammation. Thus, when FMF is untreated or insufficiently treated, the blood inflammation is strong and can exist even outside of the attacks and the risk of developing amyloidosis in the long term is then higher. This amyloidosis, called AA amyloidosis, mainly affects the kidneys and the digestive tract. Detection of AA amyloidosis is based on monitoring kidney function, including urine protein and blood creatinine levels. Confirmation of amyloidosis is based on histology via biopsy of an organ, most often the accessory salivary glands (Histology : is the medical specialty that studies organs and/or tissues under the microscope to diagnose diseases; for example : to make the diagnosis of amyloidosis, amyloid deposits must be seen on a biopsy). AA amyloidosis is secondary to prolonged blood inflammation which suggests that well -controlled blood inflammation with Colchicine makes the likelihood of amyloidosis occurrence very low. For this reason, it is essential to take Colchicineona regular basis even if you feel well.
10. How to treat FMF: main principles?
Patients should benefit from regular care and follow-up involving, as far as possible, an expert team (essential in children) in an expert center (see list of reference centers) and local caregivers (general practitioner or pediatrician, and/or nurse) and, if available, a city-hospital network. Patient and family associations can also be of great help. The current treatment of FMF does not provide a definitive cure. Its objectives are to reduce the number of attacks, to normalize the quality of life and to avoid long-term complications which are essentially renal. A background treatment is taken chronically throughout the year for life, it allows one to prevent attacks. A crisis treatment is only taken when there is a severe attack of the disease.
11. What is background treatment and is it risky?
A disease-modifying therapy is a long-term treatment, lasting several months or years, which reduces the activity of the disease. The main objectives are: 1. Improve quality of life by reducing the number of accesses. 2. Reduce the use of inflammatory drugs and avoid complications from these drugs. 3. Avoid long-term complications of the disease (inflammatory amyloidosis). Colchicine is the current standard of care for FMF. In some specific cases, other drugs called biotherapies may be used as background treatment.
12. What should I know about Colchicine?
Colchicine is a medicine made from a flower: colchicum. It acts directly on the inflammation and is very effective in preventing the occurrence of new attacks if given in sufficient doses and taken very regularly. It is not toxic for fertility or liver at therapeutic dose in FMF. The treatment of FMF is simple, inexpensive and does not involve drugs with significant side effects, as long as the doses are respected. The reference treatment is Colchicine, which prevents the occurrence of new attacks if given in sufficient doses and taken very regularly. Attacks disappear in about 60-70% of cases; the response is partial in 30% of cases and the treatment is ineffective only in very exceptional cases. Regular use of the drug prevents the development of renal complications (AA amyloidosis) that could lead to renal failure and dialysis. It is extremely important to follow the dosage prescribed by the doctor, as compliance is very important. In this case, a person with FMF can lead a normal life with a normal life expectancy. Doses should never be changed without consulting a physician first. Colchicine comes as a 1 mg tablet in boxes of 20, in other countries such as the United States and Israel, the tablet is dosed at 0.6 mg. The prescribed dose varies from 1 (0.5 mg for young children under 5 kg) to 2.5 mg/d. The dosage is adapted to each person according to their weight, disease activity and age. Colchicine does not interfere with growth in children. In case of an attack it is sometimes difficult to make all the signs disappear, but antiinflammatory and painkillers can help. In any case you should not take a higher dose of colchicine, it does not work and it is dangerous. It is necessary to rest and try to practice relaxation: mindfulness breathing, yoga, calm atmosphere by limiting sensory stimuli (noise, light etc..).
13. What is a biotherapy?
A biotherapy is a protein made by humans to block inflammation at a specific point, particularly at the level of inflammation where certain proteins from immune cells (white blood cells) are known to be produced in excess, such as interleukin 1 and interleukin 6 in FMF. Those that have marketing authorization in France for FMF are Anakinra (Kineret) and Canakinumab (Ilaris). These are 2nd intention treatments that are only given in cases of proven resistance to Colchicine correctly taken at maximum dose (a very rare situation) or in cases of AA amyloidosis with renal impairment responsible for end-stage renal failure that no longer allows Colchicine to be taken.
14. How can I manage severe pain or flare-ups while waiting
to see my doctor?
It is necessary to know how to use the medication prescribed to face these situations, starting, when it has been validated by a doctor, with anti-inflammatory medicines such as Ibuprofen, Naproxen or Indometacin at the prescribed doses (which are generally higher than those in the medical dictionaries), analgesics: Paracetamol Codeine or Tramadol. Physical measures (moving in hot water in the shower or bath, applying cold or heat to the painful area) can help. However, if it is a real flare-up or attack, a quick consultation may be necessary, often preceded by a phone call or email. Do not hesitate to contact the health care team. Many departments also have therapeutic education nurses who can answer (by phone or email) a number of questions and provide therapeutic advice. Finally, the role of the general practitioner is important, as he or she is often the "first resort" and can prescribe symptomatic treatment to reduce pain while the patient meets the specialist.
15. What are the signs that I need to go to the emergency
room?
If the attack is easily recognized, follow the emergency protocol provided and wait at home. You should go to the emergency room if: 1. Despite the treatments applied, the pain is unbearable. 2. If there are non-typical signs that may raise suspicion of a cardiac, neurological, renal or infectious complication. 3. If the crisis lasts more than 5 days. Note that there are FMF emergency cards available from doctors at the reference centers and the FAI²R network.